Activation of the insulin-like growth factor II transcription by aflatoxinB1 induced p53 mutant 249 is caused by activation of transcription complexes; implications for a gain-of-function during the formation of hepatocellular carcinoma

Aflatoxin B1 (AFB1) induced mutation of the p53 gene at codon 249 (p53mt249 ) is critical during the formation of hepatocellular carcinoma (HCC) follow ing hepatitis B virus (HBV) infection. p53mt249 markedly increases insulin- like growth factor II (IGF-II) transcription largely from promoter 4, accum ulating the fetal form of IGF-II, Modulation of the transcription factor bi nding to IGF-II P4 by wild-type p53 and p53mt249 was identified. Wild-type p53 inhibited binding of transcription factors Sp1 and TBP on the P4 promot er, while p53mt249 enhanced the formation of transcriptional complexes thro ugh enhanced DNA-protein (Spl or TBP) and protein-protein (Sp1 and TBP) int eractions. p53mt249 stimulates transcription factor Spl phosphorylation whi ch might be a cause of increased transcription factor binding on the P4 pro moter while wild-type p53 does not. Transfection of hepatocytes with p53mt2 49 impaired induction of apoptosis by the HBV-X protein and TNF-alpha. Ther efore, the blocking of apoptosis through enhanced production of IGF-II shou ld provide a favorable opportunity for the selection of transformed hepatoc ytes. These results explain the molecular basis for the genesis of HCC by p 53mt249 which was found to be induced by a potent mutagen, AFB1.